SAFETY REPORTING AND ASSESSMENT
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SAFETY REPORTING AND ASSESSMENT SANDRA BRIGHT HPRA, IRELAND MARCH 2021
Transcript of SAFETY REPORTING AND ASSESSMENT
PowerPoint PresentationHPRA, IRELAND
MARCH 2021
The Implementing Regulation for safety is not finalised
The IT database for safety reports and assessment is not finalised
Therefore the data presented in this presentation is in draft and may be updated before the go-live date
Low interventional trials Article 41 - Two possible risk adaptations to safety reporting:
- selective recording and reporting of adverse events (AEs),
- adaptations to immediate reporting from the investigator to the sponsor, for certain serious adverse events (SAEs)
May be considered for:
- IMPs that are used according to the conditions of the marketing authorisation
- IMPs that are marketed, but used differently to the conditions of the marketing authorisation
ASR usually per IMP, occasionally per CT (clinical trial)
Definition of SAEs and serious adverse reactions (SARs)
Most of the content of the ASR
Development Safety Update Report (DSUR) format as per ICH E2F
Frequency of submission (annually) and Data Lock Point (DLP)
Development International Birth Date (DIBD), alignment with International Birth Date (IBD) if authorised IMP
ASR – What is new? Co-ordinated, workshared assessment:
ASR per IMP/active substance - Assessment led by saMS (safety assessing Member State)
ASR is submitted per clinical trial (CT) – Reference Member State (RMS) takes on the role of saMS
Assessment report
Minor updates to Cumulative Summary Tabulations of Serious Adverse Events – Section 7
New sections of ASR: Region Specific Information – Section 16
Single submission of ASR to CTIS - No direct reporting to NCAs or ethics committees
Safety data for Auxiliary medicinal products can be included in section 7.2 of the ASR (Line Listings of SARs), separate ASR not needed
ASR Draft procedure
ASR procedure – all via CTIS Submission Sponsor submits ASR
Assessment Initial assessment by saMS saMS shares draft assessment report with RMS/MSC RMS/MSC raises considerations on draft assessment report, if any saMS consolidates considerations
Request for further information (RFI)
If no RFI, → end of procedure
If RFI, saMS sends RFI to sponsor
Responses Sponsor submits responses saMS assesses responses and shares updated draft assessment report with RMS/MSC RMS/MSC raises considerations, if any
End of Procedure Final assessment report shared with RMS/MSC
Sponsor notified of conclusion of assessment Recommended actions proposed by saMS, if applicable
Assessment report
Template to be downloaded for each case
Administrative information will be autopopulated
Based on word document used as part of pilot run by CZ
Assessment report
Cumulative Summary Tabulations of Serious Adverse Events – Section 7
Absolute numbers of patients that have been treated as per the column headings should be included in the text body of the ASR or preferably within the table itself
Patient treatment years may also be included
See Q7.40 of European Commission Q+A for more details
https://ec.europa.eu/health/sites/health/files /files/eudralex/vol- 10/regulation5362014_qa_en.pdf
• List of subjects who died during the reporting period
• List of subjects who dropped out of clinical trials in association with an AE during the reporting period
Already in most global ASRs as other agencies require these sections
= Now also an EU/EEA requirement
Region-Specific Information – Section 16
A high level overview of the safety review process including but not limited to:
how often data is reviewed and by whom
what type of data source/format is reviewed
what potential action may arise as a result of the surveillance process
the criteria used for determining the addition or deletion of expected terms to the RSI
See Q7.42 of European Commission Q+A for more details
Region-Specific Information – Section 16 See Q7.42 of European Commission Q+A for more details
The outcome of the safety signal review process during the ASR reporting period should be outlined. Potential new safety signals that were identified should be listed
Preferred format: PBRER table
It may not always be possible or appropriate, in which case a justification for not including this information should be provided instead (eg not enough patients treated with IMP, authorised IMP used in line with SmPC etc)
SUSARs Suspected, Unexpected, Serious Adverse Reactions
Article 42
SUSARs – What stays the same? Content of SUSAR reports (ICSR, ICH E2B)
Timelines for submission of SUSAR reports: 7 days for fatal and life-threatening SUSARs
15 days for other SUSARs
Reference Safety Information (RSI) used to determine expectedness
Reports submitted to and stored in EudraVigilance (EVCTM)
Member State Concerned (MSC) may choose to perform national assessments of SUSARs which occur in their territory
SUSARs – What is new?
Co-ordinated, workshared assessment:
Per active substance - assessment led by saMS (safety assessing Member State)
Assessment includes all SUSARs in EudraVigilance (EU SUSARs and third country SUSARs)
No direct reporting to ethics committees and NCAs (reported to EudraVigilance only, re- routing available if necessary)
Safety profile changes sent to investigators, not individual SUSARs
Draft SUSAR procedures for saMS
• SUSAR screening of EudraVigilance • Routine, regular work – weekly screen • Brief documentation of assessment of each SUSAR should be recorded • For active substance with high number of SUSARs may need to prioritise • In discussion with EMA to modify/develop EudraVigilance tools to support screen
If potential signal detected → • ‘Ad hoc’ assessment case initiated by saMS
If no signal detected → • End of assessment until the next weekly
SUSAR screen
SUSAR procedure – Signal assessment
Procedure 2: Signal assessment
If potential signal detected → • Similar workflow and steps as for ASRs, but faster timelines
• All RMS/MSC are informed and have the chance to comment/raise queries
• Request for further information (RFI), if necessary • Assessment report written by saMS • Recommended actions proposed by saMS, if applicable
Other safety notifications and information
Other safety reports may include:
Other safety notifications and information
Type of notification/information Article #
Temporary halt or early termination by the sponsor for reasons of subject safety
Article 38
• eg change in benefit risk
Article 53
• includes safety information that does fall under remit of Articles
38,42,43,53,54
• eg may come through CTFG via other committees [EMA, PRAC,
CHMP, IRN etc]
Other safety relevant notifications may be:
National issue
Linked to a specific clinical trial and not to a specific active
substance
Related to a class effect and linked to
many trials
National assessment only RMS should be informed
Procedure 2: Regular
Draft procedures for other safety notifications and information
• All MSC take immediate action • Information on an issue will be shared • No time for coordinated, workshared
assessment initially • Cooperation may be possible after initial
action
• Co-ordinated, workshared assessment • Case created in CTIS • All MSC are informed and have the
chance to comment/raise queries
Lead saMS
Lead saMS
Where there are multiple active substances involved in a safety signal:
- One saMS takes the lead and co-ordinates exchanges with other relevant saMS
- Each relevant saMS still responsible for assessment of their active substance
- Rely on volunteer for lead saMS
Example: Drug class effect
Corrective Measures
Corrective Measures – Art 77 saMS (or lead saMS) may propose recommended actions in relation to an active substance(s) following the assessment of:
SUSARs
ASR
Other safety notifications or information
As per best practice guide:
Relevant RMS to check and decide for impact on their specific trial
If all MSC agree: RMS can implement corrective measures on behalf of all MSC eg RMS requests substantial modification
If any MSC disagree: each MSC takes action themselves
However overall responsibility for a CT remains with individual MSC
Overview – Lead for workshared safety assessments
Type of safety information
Single active substance
Multiple active substances
saMS -
Other reporting obligations
Urgent safety measures
Any other safety info (not covered above)
MSC RMS saMS Lead saMS
THANKS
MARCH 2021
The Implementing Regulation for safety is not finalised
The IT database for safety reports and assessment is not finalised
Therefore the data presented in this presentation is in draft and may be updated before the go-live date
Low interventional trials Article 41 - Two possible risk adaptations to safety reporting:
- selective recording and reporting of adverse events (AEs),
- adaptations to immediate reporting from the investigator to the sponsor, for certain serious adverse events (SAEs)
May be considered for:
- IMPs that are used according to the conditions of the marketing authorisation
- IMPs that are marketed, but used differently to the conditions of the marketing authorisation
ASR usually per IMP, occasionally per CT (clinical trial)
Definition of SAEs and serious adverse reactions (SARs)
Most of the content of the ASR
Development Safety Update Report (DSUR) format as per ICH E2F
Frequency of submission (annually) and Data Lock Point (DLP)
Development International Birth Date (DIBD), alignment with International Birth Date (IBD) if authorised IMP
ASR – What is new? Co-ordinated, workshared assessment:
ASR per IMP/active substance - Assessment led by saMS (safety assessing Member State)
ASR is submitted per clinical trial (CT) – Reference Member State (RMS) takes on the role of saMS
Assessment report
Minor updates to Cumulative Summary Tabulations of Serious Adverse Events – Section 7
New sections of ASR: Region Specific Information – Section 16
Single submission of ASR to CTIS - No direct reporting to NCAs or ethics committees
Safety data for Auxiliary medicinal products can be included in section 7.2 of the ASR (Line Listings of SARs), separate ASR not needed
ASR Draft procedure
ASR procedure – all via CTIS Submission Sponsor submits ASR
Assessment Initial assessment by saMS saMS shares draft assessment report with RMS/MSC RMS/MSC raises considerations on draft assessment report, if any saMS consolidates considerations
Request for further information (RFI)
If no RFI, → end of procedure
If RFI, saMS sends RFI to sponsor
Responses Sponsor submits responses saMS assesses responses and shares updated draft assessment report with RMS/MSC RMS/MSC raises considerations, if any
End of Procedure Final assessment report shared with RMS/MSC
Sponsor notified of conclusion of assessment Recommended actions proposed by saMS, if applicable
Assessment report
Template to be downloaded for each case
Administrative information will be autopopulated
Based on word document used as part of pilot run by CZ
Assessment report
Cumulative Summary Tabulations of Serious Adverse Events – Section 7
Absolute numbers of patients that have been treated as per the column headings should be included in the text body of the ASR or preferably within the table itself
Patient treatment years may also be included
See Q7.40 of European Commission Q+A for more details
https://ec.europa.eu/health/sites/health/files /files/eudralex/vol- 10/regulation5362014_qa_en.pdf
• List of subjects who died during the reporting period
• List of subjects who dropped out of clinical trials in association with an AE during the reporting period
Already in most global ASRs as other agencies require these sections
= Now also an EU/EEA requirement
Region-Specific Information – Section 16
A high level overview of the safety review process including but not limited to:
how often data is reviewed and by whom
what type of data source/format is reviewed
what potential action may arise as a result of the surveillance process
the criteria used for determining the addition or deletion of expected terms to the RSI
See Q7.42 of European Commission Q+A for more details
Region-Specific Information – Section 16 See Q7.42 of European Commission Q+A for more details
The outcome of the safety signal review process during the ASR reporting period should be outlined. Potential new safety signals that were identified should be listed
Preferred format: PBRER table
It may not always be possible or appropriate, in which case a justification for not including this information should be provided instead (eg not enough patients treated with IMP, authorised IMP used in line with SmPC etc)
SUSARs Suspected, Unexpected, Serious Adverse Reactions
Article 42
SUSARs – What stays the same? Content of SUSAR reports (ICSR, ICH E2B)
Timelines for submission of SUSAR reports: 7 days for fatal and life-threatening SUSARs
15 days for other SUSARs
Reference Safety Information (RSI) used to determine expectedness
Reports submitted to and stored in EudraVigilance (EVCTM)
Member State Concerned (MSC) may choose to perform national assessments of SUSARs which occur in their territory
SUSARs – What is new?
Co-ordinated, workshared assessment:
Per active substance - assessment led by saMS (safety assessing Member State)
Assessment includes all SUSARs in EudraVigilance (EU SUSARs and third country SUSARs)
No direct reporting to ethics committees and NCAs (reported to EudraVigilance only, re- routing available if necessary)
Safety profile changes sent to investigators, not individual SUSARs
Draft SUSAR procedures for saMS
• SUSAR screening of EudraVigilance • Routine, regular work – weekly screen • Brief documentation of assessment of each SUSAR should be recorded • For active substance with high number of SUSARs may need to prioritise • In discussion with EMA to modify/develop EudraVigilance tools to support screen
If potential signal detected → • ‘Ad hoc’ assessment case initiated by saMS
If no signal detected → • End of assessment until the next weekly
SUSAR screen
SUSAR procedure – Signal assessment
Procedure 2: Signal assessment
If potential signal detected → • Similar workflow and steps as for ASRs, but faster timelines
• All RMS/MSC are informed and have the chance to comment/raise queries
• Request for further information (RFI), if necessary • Assessment report written by saMS • Recommended actions proposed by saMS, if applicable
Other safety notifications and information
Other safety reports may include:
Other safety notifications and information
Type of notification/information Article #
Temporary halt or early termination by the sponsor for reasons of subject safety
Article 38
• eg change in benefit risk
Article 53
• includes safety information that does fall under remit of Articles
38,42,43,53,54
• eg may come through CTFG via other committees [EMA, PRAC,
CHMP, IRN etc]
Other safety relevant notifications may be:
National issue
Linked to a specific clinical trial and not to a specific active
substance
Related to a class effect and linked to
many trials
National assessment only RMS should be informed
Procedure 2: Regular
Draft procedures for other safety notifications and information
• All MSC take immediate action • Information on an issue will be shared • No time for coordinated, workshared
assessment initially • Cooperation may be possible after initial
action
• Co-ordinated, workshared assessment • Case created in CTIS • All MSC are informed and have the
chance to comment/raise queries
Lead saMS
Lead saMS
Where there are multiple active substances involved in a safety signal:
- One saMS takes the lead and co-ordinates exchanges with other relevant saMS
- Each relevant saMS still responsible for assessment of their active substance
- Rely on volunteer for lead saMS
Example: Drug class effect
Corrective Measures
Corrective Measures – Art 77 saMS (or lead saMS) may propose recommended actions in relation to an active substance(s) following the assessment of:
SUSARs
ASR
Other safety notifications or information
As per best practice guide:
Relevant RMS to check and decide for impact on their specific trial
If all MSC agree: RMS can implement corrective measures on behalf of all MSC eg RMS requests substantial modification
If any MSC disagree: each MSC takes action themselves
However overall responsibility for a CT remains with individual MSC
Overview – Lead for workshared safety assessments
Type of safety information
Single active substance
Multiple active substances
saMS -
Other reporting obligations
Urgent safety measures
Any other safety info (not covered above)
MSC RMS saMS Lead saMS
THANKS
